Process for the production of trans-4-aminomethylcyclohexane - 1-carboxylic acid



Patented June 10, 1969 U.S. Cl. 260-514 16 Claims ABSTRACT OF THEDISCLOSURE An alkali or alkaline earth metal salt of4-N-acetamidomethylbenzoic acid is reduced with heating under pressurein the presence of Raney-nickel catalyst in an atmosphere of hydrogen toproduce an alkali or alkaline earth metal salt of4-N-acetamidomethylcyclohexane-1- carboxylic acid, and then subjectingthe product to a hydrolysis-conversion reaction by heating it at 160-250C. with an alkali agent, thereby accomplishing both the deacetylationand the transformation of the stereo conformation simultaneously toproduce trans-4-aminomethylcyclohexane-l-carboxylic acid.

The present invention relates to a process for the production oftrans-4-aminoethylcyclohexane-1-carboxylic acid.

An object of the present invention is to provide an improved andeconomical process for producing trans-4-aminomethylcyclohexane-l-carboxylic acid which has significant value asan antiplasmic agent.

Other objects and advantageous features of the present invention willappear from the following detailed description.

So far, 4-aminomethylcyclohexane-l-carboxylic acid has been known as avaluable substance for pharmaceutical use, and it is specificallypointed out in Belgian Patent No. 617,216 and British Patent No. 949,512that the compound has an antiplasmic activity and an excellenttherapeutic effect on disorders caused by the activated plasmin in vivo.However, the present inventors found that there exist two stereo isomersof the compound and that the trans-isomer has a far stronger antiplasmicactivity than the cis-isomer.

In the reaction of preparing 4-aminomethylcyclohexane-l-carboxylic acidby reducing the benzene nucleus of 4-aminomethylbenzoic acid,Raney-nickel such as any Raney-nickel of W-l to W-7 (cited in thefollowing references: The Journal of the American Chemical Society, vol.68, p. 1471 (1946), vol. 69, p. 3040 (1947) and vol. 70, p. 695 (1948)and Organic Syntheses, vol. 21, p. 15 (1941)) is far more convenientthan platinum as a catalyst to be utilized industrially. It wasrecognized, however, that if the reduction is carried out usingR-aneynickel upon 4-aminomethylbenzoic acid with its amino group andcarboxyl group unprotected, the reaction diverges from the main purposeto give only a small amount of the desired product.

The present inventors have further executed numerous experiments andstudies and have now developed a profitable process of the presentinvention for producing trans- 4-aminomethylcyclohexane-l-carboxylicacid.

In the process of the present invention, the amino group of4-aminomethylbenzoic acid is protected with acetyl group and thecarboxyl group thereof is in the form of an alkali or alkaline earthmetal salt, that is, an alkali or alkaline earth metal salt of4-N-acetamidomethylbenzoic acid is used as the starting material.

The process of the present invention may be represented by the followingreaction formula:

CHgNHCOCHa (FHzNHCOCHa CH2NH2 K K) -v H E E COOM COOM CODE wherein Mstands for an alkali metal such as sodium or potassium, or alkalineearth metal such as calcium or barium.

The process comprises reducing an alkali or alkaline earth metal salt of4-N-acetamidomethylbenzoic acid (I) with heating under pressure in thepresence of Raneynickel catalyst in an atmosphere of hydrogen to producean alkali or alkaline earth metal salt of4-N-acetamidomethylcyclohexane-l-carboxylic acid (II), and thensubjecting the product, either isolating it as the free acid (M.P. 160C.) or not isolating it, to a hydrolysisconversion reaction by heatingit at -250 C. with an alkali metal hydroxide, alkaline earth metal oxideor hydroxide to produce trans-4-aminomethylcycl0hexane-lcarboxylic acid(III), thereby accomplishing both the deacetylation and thetransformation of the stereo conformation simultaneously.

The catalytic reduction step of the present invention is carried out byshaking in an autoclave the compound (I) and Raney-nickel catalyst suchas any Raney-nickel of W-l to W-7 in a solvent such as water, analiphatic lower alcohol having 1 to 2 carbon atoms or a mixture thereofat 120 to 200 C., preferably 160 to 180 C. for 1-5 hrs. in an atmosphereof hydrogen, the initial pressure of which being 40100 atmosphericpressure, thereby the theoretical amount of hydrogen is absorbed. Then,the produced alkali or alkaline earth metal salt of 4-N-acetamidomethylcyclohexane-l-carboxylic acid (II) is, either beingisolated as its free acid or not beng isolated, subjected to the nextreaction.

The second step of the process of the present invention is carried outby heating at 180-250 C. in an autoclave the isolated product or thereaction mixture obtained above for 8-16 hrs. with an aqueous solutionof an alkali metal hydroxide such as sodium or potassium hydroxide; analkaline earth metal oxide such as calcium oxide or barium oxide; or analkaline earth metal hydroxide such as calcium hydroxide or bariumhydroxide, thereby both the deactetylation and the transformation of thestereo conformation are effected simultaneously to produce the desiredtrans-4-aminomethylcyclohexane 1 carboxylic acid. The amount of analkali metal hydroxide or an alkaline earth metal oxide or hydroxideshould be such to be necessary and enough to hydrolyze the acetal group,for example, about 1l.2 mol equivalent of the amount of the compound(II).

Thereafter, the treatment is carried out as follows in order to removeinorganic ions: (1) When an alkali metal salt of4-N-acetamidomethylbenzoic acid is used as the starting material and/ora caustic alkali is used as the hydrolyzing-transforming agent;

The reaction mixture containingtrans-4-aminomethylcyclohexane-l-carboxylic acid is passed through acolumn of a strong cation ionexchange resin, for example Diaion SK #1 (Htype) (tradename of Mitsubishi Chemical Industries Limited, Japan). Then5% of aqueous ammonia is poured into the column to eluatetrans-4-aminomethylcyclohexane-l-carboxylic acid. In this case, whenpotassium salt of 4-N-acetamidomethylbenzoic acid is used as thestarting material and potassium hydroxide is used as thehydrolyzing-transforming agent, the procedure may be convenientlysimplified as follows. The above treatment with an ion-exchange resin isnot necessary. That is, the difference in solubility between theproduced potassium acetate and potassium salt of the desired product canbe utilized, and the potassium acetate can be removed by dissolution inmethanol.

(2) When an alkaline earth metal salt of 4-N-acetamidomethylbenzoic acidis used as the starting material and/ or an alkaline earth metal oxideor hydroxide is used as the hydrolyzing -transforming agent; Before thetreatment with the ion-exchange resin, the following procedure isnecessary. An equivalent amount of an acid which is capable of forming asparingly soluble alkaline earth metal salt with the alkaline earthmetal is added to the reaction mixture to remove the alkaline earthmetal ion contained therein. As the acid, for example, sulfuric acid oroxalic acid is used and the alkaline earth metal ion contained in thereaction mixture is removed as, for example, barium sulfate or calciumoxalate. In this case, when the alkaline earth metal salt of4-N-acetamidomethylbenzoic acid and the alkaline earth metal oxide orhydroxide are used, the step of the treatment with the ionexchange resinmay be omitted. The filtrate is concentrated and the residue isrecrystallized from water-acetone or water-acetone-methanol to givecrystals of trans-4-aminomethylcyclohexane-lcarboxylic acid.

Trans-4-aminomethylcyclohexane 1 carboxylic acid which has the steroconformation:

coon a a is a colorless powder having the melting point of 380 390 C.(decomp. uncorrect. in air bath) and has characteristic infra-redabsorption at 1637, 1535 and 1383 cmf Certain salts oftrans-4-aminomethylcyclohexane-1- carboxylic acid have the followingmelting points:

HCl salt (C H NO -HCl)238-240 C. (decomp.) HBr salt (C H NO HBr)--227229C. (decomp.) Au salt (C H NO -HCl-AuCl )204-206 C. (decomp.)

Pt salt (C H NO -HCl) PtCl )254255 C. (decomp.)

Cis-isomer which has the stero conformation:

coon

Iii-1 61 H n na cn is a colorless powder having the melting point of238- 242 C. (decomp.) and has characteristic infra-red absorptions at1640, 1565, 1515, 1415 and 1310 cm.-

Trans-4-aminomethylcyclohexane-l-carboxylic acid is soluble in six timesits volume of water at room temperature but is insoluble in methanol.Furthermore, the hydrochloric acid salt ofcis-4-aminomethylcyclohexane-1- carboxylic acid is more soluble inmethanol than that of trans-4-aminomethylcyclohexane-I-carboxylic acid.

Trans-4-aminomethylcyclohexane 1 carboxylic acid produced by the processof the present invention has a potent inhibitory action on the plasminsystem, and also an excellent therapeutic effect on disorders associatedwith and/ or caused by the'activated plasmin in vivo, without anyaccompanying noticeable toxicity when applied. Some preferredembodiments of the present invention will be described in detail whereinthe examples given are for the purpose of illustrating preferredembodiments only and not for the purpose of limiting the same.

Example 1' In an aqueous solution prepared by dissolving 0.8 g. (0.02mol) of sodium hydroxide in 20 ml. of water, 3.9 g. (0.02 mol) of4-N-acetamidomethylbenzoic acid was dissolved to make a neutralsolution. In this solution, 1 g. of Raney-nickel catalyst was suspended,and the suspension was shaken in an autoclave at 170 C. for two hours inan atmosphere of hydrogen, the initial pressure of which is 82atmosphere pressure (at room temperature), thereby the theoreticalamount of hydrogen was absorbed. After cooling, the catalyst was removedby filtration. To the filtrate, 0.96 g. (0.024 mol) of sodium hydroxidewas added, and in an autoclave the solution was heated at 190200 C. for16 hours. The reaction solution was poured into a column of ml. of astrong cation ionexchange resin, Diaion SK #1. The column was washedwith water, and then trans-4-aminomethylcyclohexane-1- carboxylic acidwas eluated with 5% of aqueous ammonia. This ammoniacal eluate (positivein the Ninhydrin Reaction) was concentrated to dryness, and the residuewas recrystallized from water-acetone or water-alcohol to give 2.25 g.(yield: 71%) of crystals of trans-4-aminomethylcyclohexane-l-carboxylicacid which melt at 380- 390 C. (decomp.).

Analysis for C H O N: Calculated percent C, 61.12; H, 9.62; N, 8.91.Found percent C, 61.10; H, 9.52; N, 8.58.

Example 2 In an aqueous solution prepared by dissolving 1.1 g. (0.02mol) of potassium hydroxide in 30 ml. of water, 3.9 g. (0.02 mol) of4-N-acetamidomethylbenzoic acid was dissolved to make a neutralsolution. In this aqueous solution, 1 g. of Raney-nickel catalyst wassuspended, and the suspension was shaken in an autoclave at 180 C. forabout 2 hours in an atmosphere of hydrogen, the initial pressure ofwhich was 90 atmospheric pressure, thereby the theoretical amount ofhydrogen was absorbed. After cooling, the catalyst was removed byfiltration. To the filtrate, 1.35 g. (0.024 mol) of potassium hydroxidewas added, and in an autoclave the solution was heated at -200" C. for18 hours. After cooling, 1.45 g. (0.024 mol) of glacial acetic acid wasadded to the reaction solution to neutralize it, and then concentratedunder reduced pressure. To the residue, 15 ml. of methanol was added toremove produced potassium acetate by dissolution. The residue wasfurther treated twice with methanol to give crystalline powder. Thispowder gives, upon recrystallization from water-acetone, 2.36 g. (yield:75%) of colorless crystals oftrans-4-aminomethylcyclohexane-l-carboxylic acid which melt at 380- 390C. (decomp.). This product agreed well with an authentic sample inrespect to both infra-red spectrum and melting point.

Example 3 In 30 ml. of water, 3.9 g. (0.02 mol) of4-N-acetamidomethylbenzoic acid and 3.15 g. (0.01 mol) of bariumhydroxide were suspended, 1 g. of Raney-nickel catalyst was added tothis suspension, and the reduction was carried out'until the theoreticalamount of hydrogen was absorbed. The catalyst was removed by filtrationfrom the reaction mixture and the filtrate was concentrated to dryness.To the residue, 1.2 ml. of water and 0.96 g. (0.024 mol) of sodiumhydroxide were added, and the mixture was heated in an autoclave at190200 C. for

I 16 hours. To the reaction solution, 100 ml. of water was added, and,while warm, the theoretical amount of dilute sulfuric acid was added toprecipitate barium sulfate. After cooling, the barium sulfate wasfiltered, and the filtrate was treated with a strong cation ion-exchangeresin in the same manner as in Example 1 to give 2.55 g. (yield: 81%) ofcolorless crystals of trans-4-aminomethylcy-clohexane-l-carboxylic acidwhich melt at 380- 390 C. (decomp.).

Example 4 In 50 ml. of water, 3.9 g. (0.02 mol) of4-N-acetamidomethylbenzoic acid and 0.74 g. of calcium hydroxide weresuspended, and 1 g. of Raney-nickel catalyst was added thereto. Themixture is shaken in an autoclave at 180 C. for an hour in an atmosphereof hydrogen, the initial pressure of which being 99 atmosphere pressure.The reaction solution was concentrated under reduced pressure, 1.35 g.(0.024 mol) of potassium hydroxide was added thereto and in an autoclavethe mixture was heated at 190-200 C. for 18 hours. To the reactionsolution, 50 ml. of water was added, and then the theoretical amount ofoxalic acid was added thereto. The precipitated calcium oxalate wasremoved by filtration and the filtrate was treated with a strongion-exchange resin in the same manner as in Example 1 to give 2.08 g.(yield: 66%) of colorless crystals of trans-4-aminomethylcyclohexane-1-carboxylic acid which melt at 380-390 C. (decomp.).

Example 5 In 30 ml. of water, 3.9 g. (0.02 mol) of4-N-acetamidomethylbenzoic acid and 3.15 g. (0.01 mol) of bariumhydroxide were suspended. In an autoclave, 1 g. of Raneynickel catalystwas added thereto, and the mixture was shaken at 170-180 C. for an hourin an atmosphere of hydrogen, the initial pressure of which being 98atmospheric pressure, thereby the theoretical amount of hydrogen wasabsorbed. The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to dryness. To the residue, 12 ml.of water and 4.7 g. (0.015 mol) of barium hydroxide were added, and themixture was heated in an autoclave at 200 C. for 15 hours. To thereaction solution, 100 ml. of water was added, and, while warm, thetheoretical amount of dilute sulfuric acid was added thereto toprecipitate barium sulfate. After cooling, the precipitate was removedby filtration. The filtrate was condensed and the precipitated crystalswere recrystallized from water-acetone. They were again recrystallizedfrom water-methanol-acetone to give 2.55 g. (yield: 81%) oftrans-4-aminomethylcyclohexane-l-carboxylic acid which melts at 380-390"C. (decomp.). The product agreed well with an authentic sample inrespect to infra-red spectrum, melting point and the characteristics ofits derivatives.

Example 6 In 50 ml. of water, 3.9 g. (0.02 mol) of4-N-acetamidomethylbenzoic acid and 0.74 g. of calcium hydroxide weresuspended. In an autoclave, 1 g. of Raney-nickel was added thereto, andthe mixture was shaken at 180 C. for an hour in an atmosphere ofhydrogen, the initial pressure of which being 99 atmospheric pressure.The reaction mixture was concentrated to 20 ml., 0.85 g. (0.015 mol) ofcalcium oxide was suspended therein, and the mixture was heated in anautoclave at 200 C. for 15 hours. To the reaction solution, 50 ml. ofwater was added, and then the theoretical amount of oxalic acid wasadded thereto to precipitate calcium oxalate. The precipitate wasremoved by filtration, and the filtrate was treated in the same manneras in Example 1 to give 1.6 g. (yield: 51%) oftrans-4-aminomethylcyclohexane-1- carboxylic acid which melts at 380-390C. (decomp.).

What is claimed is:

1. A process for producing trans-4-aminomethylcyclohexane-l-carboxylicacid or a salt thereof which comprises catalytically reducing a saltselected from the group consisting of an alkali and alkaline earth metalsalt of 4-N- acetamidomethylbenzoic acid by heating at -200 C. in anautoclave in a solvent selected from the group consisting of water, analiphatic lower alcohol and a mixture thereof in the presence ofRaney-nickel catalyst in an atmosphere of hydrogen, the initial pressureof which being 40-100 atmospheres, to produce a corresponding salt of4-N-acetamidomethylcyclohexane-l-carboxylic acid; heating in anautoclave the product obtained above at -250 C. for 8-16 hours with anaqueous solution of an alkali selected from the group consisting of analkali metal hydroxide, an alkaline earth metal oxide and hydroxide; andrecovering trans-4-aminomethylcyclohexanel-carboxylic acid from thereaction mixture.

2. A process according to claim 1, in which an alkali metal is a memberselected from the group consisting of sodium and potassium.

3. A process according to claim 1, in which an alkaline earth metal is amember selected from the group consisting of barium and calcium.

4. A process according to claim 1, in which the intermediate, a salt of4-N-acetamidomethylcyclohexane-1- carboxylic acid is, without beingisolated, directly subjected to the next reaction.

5. A process for producing trans-4-aminomethylcyclohexane-l-carboxylicacid or a salt thereof which comprises catalytically reducing potassium4-N-acetarnidomethylbenzoate by heating at 120-200 C. in an autoclave inwater in the presence of Raney-nickel catalyst in an atmosphere ofhydrogen, the initial pressure of which being 40-100 atmospheres, toproduce potassium 4-N-acetamidomethylcyclohexane-l-carboxylate; heatingin an autoclave the product obtained above at ISO-250 C. for 8-16 hourswith an aqueous solution of potassium hydroxide; adding glacial aceticacid to the reaction mixture to neutralize it; concentrating themixture; and adding thereto methanol to dissolve produced potassiumacetate, whereby trans-4-aminomethylcyclohexane 1 carboxylic acidremains undissolved.

6. A process according to claim 5, in which the intermediate, potassium4-N-acetamidomethylcyclohexane-1- carboxylate is, without beingisolated, directly subjected to the next reaction.

7. A process for producing trans-4-aminomethylcyclohexane-l-carboxylicacid or a salt thereof which comprises catalytically reducing sodium4-N-acetamidomethylbenzoate by heating at 120-200 C. in an autoclave inwater in the presence of Raney-nickel catalyst in an atmosphere ofhydrogen, the initial pressure of which being 40-100 atmospheres, toproduce sodium 4-N-acetamidomethylcyclohexane-l-carboxylate; heating inan autoclave the product obtained above at 180-250 C. for 8-16 hourswith an aqueous solution of sodium hydroxide; passing the reactionmixture through a column of a strong cation ion-exchange resin; andeluating trans- 4-arninomethylcyclohexane-l-carboxylic acid with anaqueous ammonia.

8. A process according to claim 7, in which the intermediate, sodium4-N-acetamidomethylcyclohexane-1- carboxylic acid is, without beingisolated, directly subjected to the next reaction.

9. A process for producing trans-4-aminomethylcyclohexane-l-carboxylicacid or a salt thereof Which com prises catalytically reducing a memberselected from the group consisting of barium and calcium4-N-aceta-midomethylbenzoic acid be heating at 120-200 C. in anautoclave in water in the presence of -Raneynickel catalyst in anatmosphere of hydrogen, the initial pressure of which being 40-100atmospheric pressure, to produce a corresponding alkaline earth metalsalt of 4-N-acetamidomethylcyclohexane-l-carboxylic acid; heating in anautoclave the product obtained above at l80-250 C. for 8-16 hours withan aqueous solution of a member sel ected from the group consisting ofbarium oxide, calcium oxide, barium hydroxide, and calcium hydroxide;adding an acid selected from the group consisting of sulfuric acid andoxalic acid to the reaction mixture to precipitate a correspondingalkaline earth metal salt of the acid; filtering the salt and obtainingtrans-4-aminomethylcyclohexane-l-carboxylic acid from the filtrate.

10. A process according to claim 9, in which the intermediate, analkaline earth metal salt of 4-N-acetamidomethylcyclohexane-l-carboxylicacid is, without being isolated, directly subjected to the nextreaction.

11. A process for producing trans-4-aminomethylcyclohexane-l-carboxylicacid or a salt thereof which comprises providing a solution in a solventselected from the group consisting of water, aliphatic lower alcohol andmixture thereof, of a salt selected from the group of alkali andalkaline earth metal salt of 4-N-acetamidomethyl-benzoic acid; heatingsaid solution in an atmosphere of hydrogen in the presence of ahydrogenation catalyst under super-atmospheric pressure, whereby a saltof said acid is formed; then introducing into said solution analkali'selected from the group consisting of alkali metal hydroxide andalkaline earth metal oxide and hydroxide, heating said mass undersuperatmospheric pressure for a sufficient length of time to form saidtrans carboxylic acid.

12. A process according to claim 11 in which the pressure in the firststep is about 40-100 atmospheres.

13. A process according to claim 11 in which the catalyst isRaney-nickel.

14. A process according to claim 11 in which the temperature in thefirst step is about l20-200 C.

15. A process according to claim 11 in which the temperature in thesecond step is about ISO-250 C.

16. A process according to claim 11 in which the time of heating in thesecond s ep is about 8-16 hours.

References Cited UNITED STATES PATENTS 2,771,487 11/1956 Morris et a1.2605l4 OTHER REFERENCES LORRAINE A. WEINBERGER, Primary Examiner.

P. J. KILLOS, Assistant Examiner.

US. Cl. X.R.

